Simultaneous Genotyping of Seven Single-Nucleotide Polymorphisms in the MDR1 Gene by Single-Tube Multiplex Minisequencing

Responses to different drugs can vary widely among different individuals as a result of genetic variations in drug-metabolizing enzymes, transporters, receptors, and/or other cofactors. The multidrug resistance 1 (MDR1) transporter, a well-characterized member of the ATP-binding cassette superfamily, was shown to efflux a wide variety of structurally and functionally unrelated drugs, including anticancer, antiarrhythmic, antidepressant, antipsychotic, and antiviral agents. The pharmacogenetics of the MDR1 multidrug transporter have recently received much scientific attention. Several single-nucleotide polymorphisms (SNPs) have been identified in the MDR1 gene; some occur only in specific ethnic groups, whereas others occur in all ethnic groups but at significantly different allele frequencies among the different races [see Ref. (1) and references therein]. Nonetheless, the functional significance of these SNPs remains unclear. Various functional associations, some paradoxical, have been observed between the synonymous SNP (exon 26 3435C→T) and MDR1 protein expression and plasma drug concentrations (2)(3)(4)(5), drug-induced side effects (6), and drug response (7). The SNP exon 26 3435T allele has been associated with lower MDR1 expression in the duodenum (2), leukocytes (5), and placental tissues (8), leading to lower rhodamine efflux (5) and increased plasma digoxin concentrations (2). In addition, early-onset Parkinson patients have higher frequency of the SNP exon 26 3435T allele compared with late-onset patients or unaffected controls (9). However, although this same allele has been associated with lower MDR1 expression in peripheral blood mononuclear cells and better response to HIV-1 drugs, it has also been associated with lower plasma concentrations of nelfinavir (7). Additionally, the SNP exon 26 3435T allele has been associated with an increased risk of nortriptyline-induced postural hypertension, although blood concentrations of nortriptyline in these individuals were not significantly different from those in individuals carrying the C allele (6). Furthermore, no association has been demonstrated between the …